Mounir Ait-Khaled, 99767- 1 The Predictive Quality of Genotype and Phenotype Data on Virological Response to Salvage Therapy in HIV-1 Infected Patients

Mounir Ait-Khaled, 99767- 1

The Predictive Quality of Genotype and The Predictive Quality of Genotype and Phenotype Data on Virological Response to Phenotype Data on Virological Response to Salvage Therapy in HIV-1 Infected Patients Salvage Therapy in HIV-1 Infected Patients

(CNAA2007)(CNAA2007)

Resistance Collaborative Group ReanalysisResistance Collaborative Group Reanalysis

M Ait-Khaled, J Scott, L Dix, J Falloon,M Ait-Khaled, J Scott, L Dix, J Falloon,A Rakik, P Griffin, D Thomas and L Pedneault A Rakik, P Griffin, D Thomas and L Pedneault

for the CNA2007 study team for the CNA2007 study team


Background InformationBackground Information

• Open-label, single arm trial of ABC (300mg BID) + APV Open-label, single arm trial of ABC (300mg BID) + APV (1200mg BID) + EFV (600mg QD) as salvage therapy(1200mg BID) + EFV (600mg QD) as salvage therapy

• 101 subjects enrolled and 99 subjects exposed to 101 subjects enrolled and 99 subjects exposed to study drugsstudy drugs

• Subjects had extensive prior antiretroviral experience Subjects had extensive prior antiretroviral experience – 44% were nNRTI experienced44% were nNRTI experienced– 60% had prior experience with 3-4 PIs60% had prior experience with 3-4 PIs– 72% had prior experience with 4-5 NRTIs72% had prior experience with 4-5 NRTIs

• DemographyDemography– Median Age 42 yearsMedian Age 42 years– 84% males / 16% Females84% males / 16% Females– 82% White / 12% Black / 6% Other82% White / 12% Black / 6% Other


MethodsMethods

• Plasma HIV-1 RNA: AmplicorPlasma HIV-1 RNA: Amplicor

• Genotyping; Plasma population Genotyping; Plasma population sequencing (ABI)sequencing (ABI)

• Phenotyping: Antivirogram Phenotyping: Antivirogram (Recombinant Virus Assay)(Recombinant Virus Assay)

• End Point: Week 24 HIV-1 RNA > 400 End Point: Week 24 HIV-1 RNA > 400 copies/mLcopies/mL

• Statistical analysis according to DAPStatistical analysis according to DAP


Baseline Characteristics of Study Baseline Characteristics of Study PopulationPopulation

GenotypeGenotype Phenotype Phenotype PopulationPopulation Population Population

(N=94)(N=94) (n=64)(n=64)

Median HIV-1 RNAMedian HIV-1 RNA 5.0585.058 5.1265.126log 10 copies/mLlog 10 copies/mL (3.36-6.60)(3.36-6.60) (3.99-6.33)(3.99-6.33)

(range)(range)

Median CD4 CountMedian CD4 Count 160160 124124cells/µL (range)cells/µL (range) (10-782)(10-782) (10-607)(10-607)

Prior NNRTI UsagePrior NNRTI Usage 40%40% 42%42%


Baseline HIV-1 Genotypes and Phenotypes Baseline HIV-1 Genotypes and Phenotypes of the Study Populationof the Study Population

• 75% of isolates had 75% of isolates had 4 NRTI-associated mutations 4 NRTI-associated mutations

• 45% had 45% had 1 NNRTI-associated mutation (21% 1 NNRTI-associated mutation (21% 2) 2)

• 81% had 81% had 4 PI-associated mutation (50% 4 PI-associated mutation (50% 5) 5)

AbacavirAbacavir AmprenavirAmprenavir EfavirenzEfavirenz

<< 4 Fold 4 Fold 45% 45% 58% 58% 67% 67%

<< 10 Fold 10 Fold 94% 94% 86% 86% 73% 73%


Genotypic Univariate Analysis:Genotypic Univariate Analysis:Odds Ratio of Virological FailureOdds Ratio of Virological Failure

0.1

1

10

100 Dropouts as Failures

l Dropouts as Censored

Baseline RNAPotent

New Drug GSS


Genotypic Multivariate Analysis:Genotypic Multivariate Analysis:Odds Ratio of Virological FailureOdds Ratio of Virological Failure

GSS with Additional Baseline CovariatesGSS with Additional Baseline Covariates

0.1

1

10



Baseline RNAPotent

New Drug GSS



Number of Mutations by Class withNumber of Mutations by Class withAdditional Baseline CovariatesAdditional Baseline Covariates

0.1

1

10



BaselineRNA

PotentNew Drug

# NRTIMuts

# NNRTIMuts

# PIMuts


Phenotypic Univariate Analysis:Phenotypic Univariate Analysis:Odds Ratio of Virological FailureOdds Ratio of Virological Failure

0.1

1

10



BaselineRNA

PotentNew Drug

PSS4 FR

Cutoff

PSS10 FRCutoff


Phenotypic Multivariate Analysis:Phenotypic Multivariate Analysis:Odds Ratio of Virological FailureOdds Ratio of Virological Failure

PSS with Additional Baseline CovariatesPSS with Additional Baseline Covariates

0.1

1

10

100

Dropouts as Failures l Dropouts as Censored

BaselineRNA

PotentNew Drug

PSS4-FRCutoff

4-FR Cutoff

n

n

n

l

l

l

0.1

1

10

100

BaselineRNA

PotentNew Drug

PSS10-FRCutoff

10-FR Cutoff



Class Phenotypic Sensitivities withClass Phenotypic Sensitivities withAdditional Baseline CovariatesAdditional Baseline Covariates

0.01

0.1

1

10



BaselineRNA

PotentNew Drug

# NRTISens

4-FR Cutoff

# NNRTISens

4-FR Cutoff

# PISens

4-FR Cutoff


ConclusionsConclusions

• Genotypic Sensitivity Score was the only Genotypic Sensitivity Score was the only predictor of virological response in the model predictor of virological response in the model with Baseline RNA, New Drug Covariate and with Baseline RNA, New Drug Covariate and GSS (p=0.07).GSS (p=0.07).

• The number of NRTI and NNRTI mutations The number of NRTI and NNRTI mutations were also predictors of virological response were also predictors of virological response after adjusting for baseline viral load and new after adjusting for baseline viral load and new drug covariate (p=0.03, 0.008, respectively).drug covariate (p=0.03, 0.008, respectively).

ContinuedContinued


Conclusions (continued)Conclusions (continued)

• In the univariate phenotypic analysis of this In the univariate phenotypic analysis of this study the 4-fold but not the 10-fold cutoff was study the 4-fold but not the 10-fold cutoff was associated with virological failure.associated with virological failure.

• In heavily pre-treated patients the Phenotypic In heavily pre-treated patients the Phenotypic Sensitivity Score using the 4-fold cutoff was Sensitivity Score using the 4-fold cutoff was the best predictor of response, independent the best predictor of response, independent of baseline viral load and new drug covariate.of baseline viral load and new drug covariate.


InvestigatorsInvestigators

Joseph Eron, MDJoseph Eron, MD

Judy Falloon, MDJudy Falloon, MD

Judith Feinberg, MDJudith Feinberg, MD

Timothy Flanigan, MDTimothy Flanigan, MD

Scott Hammer, MDScott Hammer, MD

Susan Jacobson, MDSusan Jacobson, MD

Peter Kraus, MDPeter Kraus, MD

Robert Murphy, MDRobert Murphy, MD

Ramon Torres, MDRamon Torres, MD

Glaxo WellcomeGlaxo Wellcome

Mounir Ait-Khaled, PhDMounir Ait-Khaled, PhD

Seth Hetherington, MDSeth Hetherington, MD

Judith Millard, PhDJudith Millard, PhD

Louise Pedneault, MDLouise Pedneault, MD

Mike Rogers, PhDMike Rogers, PhD

William Spreen, Pharm DWilliam Spreen, Pharm D

Deborah Thomas, PhDDeborah Thomas, PhD

Margaret Tisdale, PhDMargaret Tisdale, PhD

Josie Wolfram, PhDJosie Wolfram, PhD

Wendy Snowden, PhDWendy Snowden, PhD

Abdelrahim Rakik, MScAbdelrahim Rakik, MSc

Philip Griffin, BScPhilip Griffin, BSc

NIHNIHHenry Masur, MDHenry Masur, MD

DuPont PharmaDuPont PharmaDoug Manion, MDDoug Manion, MDBetsy Dusak Betsy Dusak

StatisticsStatisticsJanna ScottJanna ScottLynn DixLynn DixGillian AmphlettGillian AmphlettRichard Myers, MScRichard Myers, MSc

AcknowledgementAcknowledgement


BackupsBackups



Number of MutationsNumber of Mutations

0.1

1

10



# NRTI Muts # PI Muts# NNRTI Muts



Class Phenotypic SensitivitiesClass Phenotypic Sensitivities

0.01

0.1

1

10



# NRTI Sens # PI Sens# NNRTI Sens

Documents

Mounir Ait-Khaled, 99767- 1 The Predictive Quality of Genotype and Phenotype Data on Virological Response to Salvage Therapy in HIV-1 Infected Patients